Lanthanides, the 14 4f-block elements plus Lanthanum, have been extensively used to study the structure and biochemical properties of metalloproteins. The characteristics of lanthanides within the lanthanide series are similar, but not identical. The present research offers a systematic investigation of the ability of the entire Ln³⁺ series to substitute for Ca²⁺ in biological systems. A well-calibrated DFT/PCM protocol is employed in studying the factors that control the metal selectivity in biological systems by modeling typical calcium signaling/buffering binding sites and elucidating the thermodynamic outcome of the competition between the “alien” La³⁺/Ln³⁺ and “native” Ca²⁺, and La³⁺ − Ln³⁺ within the lanthanide series. The calculations performed reveal that the major determinant of the Ca²⁺/Ln³⁺ selectivity in calcium proteins is the net charge of the calcium binding pocket; the more negative the charge, the higher the competitiveness of the trivalent Ln³⁺ with respect to its Ca²⁺ contender. Solvent exposure of the binding site also influences the process; buried active centers with net charge of −4 or −3 are characterized by higher Ln³⁺ over Ca²⁺ selectivity, whereas it is the opposite for sites with overall charge of −1. Within the series, the competition between La³⁺ and its fellow lanthanides is determined by the balance between two competing effects: electronic (favoring heavier lanthanides) and solvation (generally favoring the lighter lanthanides).

Strontium salts are used for treatment of osteoporosis and bone cancer, but their impact on calcium-mediated physiological processes remains obscure. To explore Sr²⁺ interference with Ca²⁺ binding to proteins of the EF-hand family, we studied Sr²⁺/Ca²⁺ interaction with a canonical EF-hand protein, α-parvalbumin (α-PA). Evaluation of the equilibrium metal association constants for the active Ca²⁺ binding sites of recombinant human α-PA (‘CD’ and ‘EF’ sites) from fluorimetric titration experiments and isothermal titration calorimetry data gave 4 × 10⁹ M⁻¹ and 4 × 10⁹ M⁻¹ for Ca²⁺, and 2 × 10⁷ M⁻¹ and 2 × 10⁶ M⁻¹ for Sr²⁺. Inactivation of the EF site by homologous substitution of the Ca²⁺-coordinating Glu in position 12 of the EF-loop by Gln decreased Ca²⁺/Sr²⁺ affinity of the protein by an order of magnitude, whereas the analogous inactivation of the CD site induced much deeper suppression of the Ca²⁺/Sr²⁺ affinity. These results suggest that Sr²⁺ and Ca²⁺ bind to CD/EF sites of α-PA and the Ca²⁺/Sr²⁺ binding are sequential processes with the CD site being occupied first. Spectrofluorimetric Sr²⁺ titration of the Ca²⁺-loaded α-PA revealed presence of secondary Sr²⁺ binding site(s) with an apparent equilibrium association constant of 4 × 10⁵ M⁻¹. Fourier-transform infrared spectroscopy data evidence that Ca²⁺/Sr²⁺-loaded forms of α-PA exhibit similar states of their COO⁻ groups. Near-UV circular dichroism (CD) data show that Ca²⁺/Sr²⁺ binding to α-PA induce similar changes in symmetry of microenvironment of its Phe residues. Far-UV CD experiments reveal that Ca²⁺/Sr²⁺ binding are accompanied by nearly identical changes in secondary structure of α-PA. Meanwhile, scanning calorimetry measurements show markedly lower Sr²⁺-induced increase in stability of tertiary structure of α-PA, compared to the Ca²⁺-induced effect. Theoretical modeling using Density Functional Theory computations with Polarizable Continuum Model calculations confirms that Ca²⁺-binding sites of α-PA are well protected against exchange of Ca²⁺ for Sr²⁺ regardless of coordination number of Sr²⁺, solvent exposure or rigidity of sites. The latter appears to be a key determinant of the Ca²⁺/Sr²⁺ selectivity. Overall, despite lowered affinity of α-PA to Sr²⁺, the latter competes with Ca²⁺ for the same EF-hands and induces similar structural rearrangements. The presence of a secondary Sr²⁺ binding site(s) could be a factor contributing to Sr²⁺ impact on the functional activity of proteins.

Due to the similarity in the basic coordination behavior of their mono-charged cations, silver biochemistry is known to be linked to that of copper in biological systems. Still, Cu⁺/²⁺ is an essential micronutrient in many organisms, while no known biological process requires silver. In human cells, copper regulation and trafficking is strictly controlled by complex systems including many cytosolic copper chaperones, whereas some bacteria exploit the so-called “blue copper” proteins. Therefore, evaluating the controlling factors of the competition between these two metal cations is of enormous interest. By employing the tools of computational chemistry, we aim to delineate the extent to which Ag⁺ might be able to compete with the endogenous copper in its Type I (T1Cu) proteins, and where and if, alternatively, it is handled uniquely. The effect of the surrounding media (dielectric constant) and the type, number, and composition of amino acid residues are taken into account when modelling the reactions in the present study. The obtained results clearly indicate the susceptibility of the T1Cu proteins to a silver attack due to the favorable composition and geometry of the metal-binding centers, along with the similarity between the Ag⁺/Cu⁺-containing structures. Furthermore, by exploring intriguing questions of both metals’ coordination chemistry, an important background for understanding the metabolism and biotransformation of silver in organisms is provided.

With the emergence of host-guest systems, a novel branch of complexation chemistry has found wide application in industries such as food, pharmacy, medicine, environmental protection and cosmetics. Along with the extensively studied cyclodextrins and calixarenes, the innovative cucurbiturils (CB) have enjoyed increased popularity among the scientific community as they possess even better qualities as cavitands as compared to the former molecules. Moreover, their complexation abilities could further be enhanced with the assistance of metal cations, which can interestingly exert a dual effect on the complexation process: either by competitively binding to the host entity or cooperatively associating with the CB@guest structures. In our previous work, two metal species (Mg²⁺ and Ga³⁺) have been found to bind to CB molecules in the strongest fashion upon the formation of host–guest complexes. The current study focuses on their role in the complex formation with three dye molecules: thiazole orange, neutral red, and thioflavin T. Various key factors influencing the process have been recognized, such as pH and the dielectric constant of the medium, the cavity size of the host, Mⁿ⁺ charge, and the presence/absence of hydration shell around the metal cation. A well-calibrated DFT methodology, solidly based and validated and presented in the literature experimental data, is applied. The obtained results shed new light on several aspects of the cucurbituril complexation chemistry.

Cyclodextrins (CDs) are host systems with inherent capability for inclusion complex formation with various molecular entities, mostly hydrophobic substances. Host CDs are highly accommodative to water molecules as well and usually contain water in the native state. There is still an ongoing discussion on both the total number of water molecules and their preferred binding position inside the cavities of the CDs. To understand the hydration/dehydration properties of γ-CD (the largest of the three most abundant native CDs), the main experimental methods applied in this study were differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). By coupling these techniques with density functional theory (DFT) calculations we try to shed some light on the mechanism of the γ-CD hydration and to address some unanswered questions: (i) what are the preferable locations for water molecules in the macrocyclic cavity (“hot spots”); (ii) what are the major factors contributing to the stability of the water cluster in the CD interior; (iii) what type of interactions (i.e., water–water and/or water–CD walls) contribute to the stability of the water assemble; (iv) how does the mechanism of the γ-CD hydration compare with those of its α-CD and β-CD counterparts.